calicheamicin-gamma(1)i and Leukemia--Myeloid

Gemtuzumab ozogamicin (GO) is an immunoconjugate that binds to CD33 on the surface of acute myeloid leukaemia (AML) blasts and, after internalisation, releases a cytotoxic drug, calicheamicin. GO is approved by the US Food and Drug Administration for the treatment of CD33-positive AML at first relapse in patients 60 years and older who are not candidates for other cytotoxic therapy. GO as a single agent has low antileukaemic activity. When given to patients meeting the criteria noted above, it produces a complete response (CR) rate of only 12%, with another 12% achieving CR with inadequate platelet recovery (CRp). The median survival of patients treated with GO monotherapy is 11.2 months. GO therapy at 9 mg/m(2) is complicated with hepatic veno-occlusive disease in 5-10% of patients, particularly prior to or following stem cell transplantation. GO at lower doses combined with chemotherapy as induction or postremission therapy is promising, however, and phase III trials are ongoing. GO is probably most active in acute promyelocytic leukaemia (APL). It is used for induction regimens in high-risk APL and for the elimination of minimal residual APL. Case reports suggest that GO also has activity in CD33-positive acute lymphoblastic leukaemia. In conclusion, single agent GO can induce responses in patients with CD33-positive AML in first recurrence. The future of GO is its use in combination with other cytotoxic agents. Ongoing clinical trials may better define the role of GO combinations, particularly in untreated AML.

Topics: Acute Disease; Aminoglycosides; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance; Enediynes; Gemtuzumab; Humans; Immunotoxins; Leukemia, Myeloid; Protein Binding; Randomized Controlled Trials as Topic; Recurrence; Sialic Acid Binding Ig-like Lectin 3

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Area Under Curve; Cell Adhesion Molecules; Enediynes; Female; Gemtuzumab; Humans; Immunotoxins; Infusions, Intravenous; Leukemia, Myeloid; Male; Membrane Glycoproteins; Metabolic Clearance Rate; Middle Aged; Models, Biological; Recurrence; Sialic Acid Binding Ig-like Lectin 3

Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33(+) AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3, 3'-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Cell Count; Enediynes; Female; Hematopoiesis; Humans; Immunoconjugates; Injections, Intravenous; Leukemia, Myeloid; Male; Middle Aged; Sialic Acid Binding Ig-like Lectin 3; Treatment Outcome

Topics: Acute Disease; Aminoglycosides; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enediynes; Gemtuzumab; Humans; Immunotoxins; Leukemia, Myeloid; Methotrexate; Neoplasm Proteins; Tumor Cells, Cultured